The present invention relates to 5,11-dihydrodibenzo[b,e][1,4]oxazepine derivatives, stereoisomers thereof, pharmacologically acceptable salts thereof or hydrates thereof, which have a calcium channel blocking activity and are useful for the therapy and the treatment of the digestive tract abnormal moving function diseases, especially the intestinal diseases such as the irritable bowel syndrome as well as a pharmaceutical composition containing the same as an active ingredient.
For example, European Patent No. 0404359A1 discloses that 5,11-dihydrodibenzo[b,e][1,4]thiazepine derivatives are useful as a calcium channel blocker having a selectivity for the gastrointestinal tract. Quinn, P. et al., Brit. J. Pharmacol. 1994, 112(Suppl.), Abst p573 and Wallis, R. M. et al., Brit. J. Pharmacol. 1994, 112(Suppl.), Abst p574 disclose that (S)-5-[1-[2-(Methoxyphenyl)ethyl]pyrrolidin-2-ylmethyl]-5,11-dihydrodibenzo[b,e][1,4]thiazepine maleate which is one of the above-mentioned derivatives has the same activity as mentioned above. However, the above-mentioned compounds are problematic in that they exhibit an anticholinergic activity which gives a side effect such as hydrodipsia, mydriasis or the like.
In recent years, as the social environment has become complicated, a lot of people have come to be under great stress, and there have been a large number of patients suffering from an irritable bowel syndrome of which main symptoms are abnormal bowel movement, abdominal pain and the like. To cope with such diseases, an anticholinergic agent, a laxative agent, an antidiarrheal drug, a drug for controlling intestinal function, a mucosa paralyzant, a drug for controlling an intestinal tract moving function, an agent of controlling an autonomic nerve, a herb medicine, an antianxiety agent, an antidepressant, a hypnotic agent, a neuroleptic agent and the like have been used so far. However, clinical effects of these agents are insufficient, and these agents are not necessarily satisfactory in view of the side effects. Accordingly, the development of a new type of a drug which is free of a side effect and which has an excellent activity of improving a digestive tract moving function has been in demand.
An object of the present invention is to provide a novel compound having an excellent activity of improving a digestive tract moving function.
Another object of the present invention is to provide a novel compound which is free of a side effect and which has an excellent activity of improving a digestive tract moving function.
Another object of the present invention is to provide a pharmaceutical composition containing said compound.
These and other objects of the present invention will be apparent from the following description and examples.
It has been considered that since a calcium channel blocker exhibits an activity of inhibiting contraction of a smooth muscle, it is effective for treating diseases caused by abnormal acceleration of contraction of the intestinal tract, for example, intestinal diseases such as an irritable bowel syndrome. In fact, it has been reported that a calcium channel blocker such as nicardipine, verapamil or the like is effective for treating an irritable bowel syndrome [Am. J. Gastroenterol., 80, 317 (1985), Gut., 28, 1609 (1987), J. Clin, Psychiatry., 48, 388 (1987), and Pharmacol. Ther., 60, 121 (1993)]. Actually, however, this calcium channel blocker is little applied clinically owing to its main effect on the heart blood vessel system. Under these circumstances, the present inventors have assiduously conducted investigations to develop a calcium channel blocker which exhibits a low toxicity, namely which gives no influence to the heart blood vessel system and which has a selectivity for the intestinal tract as an agent of treating the digestive tract abnormal moving function diseases, especially the intestinal diseases such as the irritable bowel syndrome. As a result, they have found that a compound represented by formula [I] gives a calcium channel antagonism selectively to the intestinal tract, and that it is effective as an agent of improving a digestive tract abnormal moving function which is almost free from side effects such as an anticholinergic activity, a decrease in the body temperature and the like. These findings have led to the completion of the present invention. That is, the present invention relates to 5,11-dihydrodibenzo[b,e][1,4]oxazepine derivatives represented by formula [I]: 
wherein R1 and R2 are the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, a hydroxy group or a lower alkoxy group, or R1 and R2 together form xe2x80x94O(CH2)nOxe2x80x94 in which n is 1, 2 or 3, R3 represents a hydrogen atom or hydroxy group, R4 and R5 are the same or different and each represents a hydrogen atom or hydroxy group, or R4 and R5 together form xe2x95x90O group, stereoisomers thereof, pharmacologically acceptable salts thereof, or hydrates thereof as well as a pharmaceutical composition containing the same as an active ingredient.
In formula [I], examples of the halogen atom of R1 and R2 include fluorine and chlorine atoms. Examples of the lower alkoxy group include an alkoxy group having 1 to 5 carbon atoms such as methoxy, ethoxy and n-propoxy groups. Examples of xe2x80x94O(CH2)n Oxe2x80x94 include methylenedioxy, ethylenedioxy and propylenedioxy groups. Among these, fluorine atom is preferable as the halogen atom, and an alkoxy group having 1 to 3 carbon atoms is preferable as the lower alkoxy group.
In the present invention, it is preferable that R31 R4 and R5 in the formula [I] each be a hydrogen atom. In this connection, it is preferable that R1 and R2 in the formula [I] be the same or different and each represent a hydrogen atom, a halogen atom or a lower alkoxy group, provided that the both R1 and R2 do not represent a hydrogen atom at the same time. Furthermore, it is more preferable that R1 represent a hydrogen atom, and R2 represent a halogen atom or a lower alkoxy group. Among these, the most preferred are (R)-(+)-5,11-dihydro-5-[1-(4-methoxyphenethyl)-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]oxazepine having the following formula, pharmacologically acceptable salts thereof and hydrates thereof. 
(R)-(+)-5,11-dihydro-5-[1-(4-fluorophenethyl)-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]oxazepine, pharmacologically acceptable salts thereof and hydrates thereof are also the most preferable.
Examples of the pharmacologically acceptable salts of Compounds [I] in the present invention include mineral (inorganic) acid salts such as a hydrochloride, a hydrobromide, a sulfate and a phosphate; and organic acid salts such as an acetate, a lactate, a fumarate, a maleate, a malate, a tartrate, a citrate, an oxalate, an aspartate and a methanesulfonate. Among these, inorganic acid salt is preferred.
Compounds [I] of the present invention have one asymmetric carbon atom, and can include optical isomers. These optical isomers, mixtures thereof or racemic compounds thereof are included in Compounds [I] of the present invention. In this connection, the R form is preferred. Further, Compounds [I] and the pharmacologically acceptable salts thereof in the present invention may be present in the form of hydrates or solvates. Thus, these hydrates or solvates are also included in the present invention.
Compound [I] of the present invention can be produced as schematically shown below, for example. 
wherein R1 to R5 are as defined above, and X represents a chlorine atom, a bromine atom or an iodine atom. In this respect, it is preferable that R3, R4 and R5 each represents a hydrogen atom.
Compound [I] of the present invention can be produced by reacting Compound [II] with a halogen compound represented by formula [III] in a solvent in the presence of a base.
Preferable examples of the reaction solvent include dimethyl sulfoxide; amides such as N,N-dimethylformamide; ethers such as tetrahydrofuran, diethyl ether, dioxane and 1,2-dimethoxyethane; toluene; xylene and benzene. Examples of the base include sodium hydride, potassium hydride, lithium diisopropylamide, n-butyl lithium, sodium methoxide and potassium tert-butoxide.
The reaction temperature is usually between 0xc2x0 C. and 150xc2x0 C., preferably between room temperature and 100xc2x0 C.
The reaction time varies depending on the reaction temperature or the type of the solvent. It is usually between 1 and 150 hours.
The amount of Compound [III] or the amount of the base is 1 mol or more, preferably between 1 and 5 mols per mol of Compound [II].
Compound [II] used as a starting material in the above-mentioned reaction can be formed by a known method [J. Med. Chem., 7, 609 (1964)].
The halogen compound of formula [III] can be produced according to a known method [EP 0404359A1].
The stereochemistry of the compounds in the present invention was determined on the basis of the reaction mechanism described in the literature [EP 0404359A1 and Tetrahedron, 37, 2173 (1981)].
When the compound of the present invention is used in the form of pharmaceutical preparations or compositions, it is possible that the above-mentioned compound is mixed with preparation auxiliaries such as an excipient, a carrier, a diluent and the like as required, the mixture is formed into tablets, capsules, granules, grains, powders, pills, syrups, suspensions, emulsifiers, ointments, suppositories, injections or the like, and the resulting preparations are administered either orally or parenterally. In this connection, it is preferable that the pharmaceutical preparations or compositions contain the compound of the present invention as an active ingredient, and pharmaceutically acceptable carrier and/or diluent. Examples of the carrier and diluent include glucose, sucrose, lactose, talc, silica, cellulose, methyl cellulose, starch, gelatin, ethylene glycol, polyethylene glycol, glycerin, ethanol, water, fat and oil.
The dose and the number of administrations of the compound in the present invention can be selected, as required, depending on the type of the disease and the age, the weight and the like of the patient. For example, when the compound of the present invention is orally administered to a grown-up patient suffering from an intestinal disease such as an irritable bowel syndrome, it may be administered at a dose of from approximately 0.1 to 1,000 mg a day either once or in divided portions.